This research proposal addresses the function of SPARC (secreted protein acidic and rich in cysteine) in the maintenance and repair of collagenous matrices in the skin. The motivation for these Aims is based on the observations that the skin of SPARC-null mice is lower in tensile strength than that of wild-type mice and that the tails of SPARC-null animals have curly tips. Both of these phenotypes are consistent with aberrant collagen matrices. In addition, recent data from their laboratory indicate that SPARC regulates collagen and TGF-B in renal cells and tissue. They hypothesize that SPARC serves to modulate cellular interaction with collagen-rich matrices. First, the molecular basis of skin fragility and tail abnormalties will be investigated by testing the function of SPARC in 1) collagen fibrillogenesis, 2) procollagen processing, 3) matrix metalloprotease regulation, and 4) cellular rearrangement of collagen gels. Second, the potential function of SPARC in the regulation the activity of transglutaminase, an enzyme that lends stability to the ECM by the formation of covalent crosslinks and modulates the activity of TGF-B by cross-linking the cytokine to the ECM, will be addressed. Third, how alterations in collagen fibril formation or degradation and/or changes in transglutaminase activity affect animal models of skin repair and foreign body response in SPARC-null versus wild-type animals will be investigated. These studies have the potential to contribute to the understanding of wound healing, biocompatibility, and the pathogenesis of collagen disorders such as Ehlers-Danlos Syndrome that could accelerate the progress and design of new therapies in the treatment and resolution of these events.